tbuckley/cabot-search huggingface dataset:
Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial
Authors: Constantin Roder, Walter Stummer, Jan Coburger, Moritz Scherer, Patrick Haas, Christian von der Brelie, Marcel Alexander Kamp, Mario Löhr, Christina A. Hamisch, Marco Skardelly, Torben Scholz, Stephanie Schipmann, Julian Rathert, Catrin Marlene Brand, Andrej Pala, Ulrike Ernemann, Florian Stockhammer, Rüdiger Gerlach, Paul Kremer, Roland Goldbrunner, Ralf-Ingo Ernestus, Michael Sabel, Veit Rohde, Ghazaleh Tabatabai, Peter Martus, Sotirios Bisdas, Oliver Ganslandt, Andreas Unterberg, Christian Rainer Wirtz, Marcos Tatagiba
Journal: Journal of Clinical Oncology (2023)

PURPOSE Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm ( P = .79). Incision-suture times ( P &lt; .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS ( P &lt; .001) and OS ( P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors ( P = .006). CONCLUSION We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
Metabolomic Differences in Connective Tissue Disease–Associated Versus Idiopathic Pulmonary Arterial Hypertension in the <scp>PVDOMICS</scp> Cohort
Authors: Catherine E. Simpson, Anna R. Hemnes, Megan Griffiths, Gabriele Grunig, W. H. Wilson Tang, Joe G. N. Garcia, John Barnard, Suzy A. Comhair, Rachel L. Damico, Stephen C. Mathai, Paul M. Hassoun
Journal: Arthritis & Rheumatology (2023)

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD-PAH versus patients with IPAH that might underlie these observed clinical differences.
Risk-Adapted Neoadjuvant Chemoradiotherapy in Rectal Cancer: Final Report of the OCUM Study
Authors: Reinhard Ruppert, Theodor Junginger, Rainer Kube, Joachim Strassburg, Andreas Lewin, Joerg Baral, Christoph A. Maurer, Joerg Sauer, Johannes Lauscher, Guenther Winde, Rena Thomasmeyer, Sigmar Stelzner, Cornelius Bambauer, Soenke Scheunemann, Axel Faedrich, Daniel Wollschlaeger, Susanne Merkel
Journal: Journal of Clinical Oncology (2023)

We investigated whether neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer can be restricted to those at high risk of locoregional recurrence (LR) without compromising oncological outcomes.In a prospective multicenter interventional study, patients with rectal cancer (cT2-4, any cN, cM0) were classified according to the minimal distance between the tumor, suspicious lymph nodes or tumor deposits, and mesorectal fascia (mrMRF). Patients with a distance >1 mm underwent up-front total mesorectal excision (TME; low-risk group), whereas those with a distance ≤1 mm and/or cT4 and cT3 tumors in the lower rectal third received nCRT followed by TME surgery (high-risk group). The primary end point was 5-year LR rate.Of the 1,099 patients included, 884 (80.4%) were treated according to the protocol. A total of 530 patients (60%) underwent up-front surgery, and 354 (40%) had nCRT followed by surgery. Kaplan-Meier analyses revealed 5-year LR rates of 4.1% (95% CI, 2.7 to 5.5) for patients treated per protocol, 2.9% (95% CI, 1.3 to 4.5) after up-front surgery, and 5.7% (95% CI, 3.2 to 8.2) after nCRT followed by surgery. The 5-year rate of distant metastases was 15.9% (95% CI, 12.6 to 19.2) and 30.5% (95% CI, 25.4 to 35.6), respectively. In a subgroup analysis of 570 patients with lower and middle rectal third cII and cIII tumors, 257 (45.1%) were at low-risk. The 5-year LR rate in this group was 3.8% (95% CI, 1.4 to 6.2) after up-front surgery. In 271 high-risk patients (involved mrMRF and/or cT4), the 5-year rate of LR was 5.9% (95% CI, 3.0 to 8.8) and of metastases 34.5% (95% CI, 28.6 to 40.4); disease-free survival and overall survival were the worst.The findings support the avoidance of nCRT in low-risk patients and suggest that in high-risk patients, neoadjuvant therapy should be intensified to improve prognosis.
Gradients of neurotransmitter receptor expression in the macaque cortex
Authors: Sean Froudist-Walsh, Ting Xu, Meiqi Niu, Lucija Rapan, Ling Zhao, Daniel S. Margulies, Karl Zilles, Xiao-Jing Wang, Nicola Palomero-Gallagher
Journal: Nature Neuroscience (2023)

Abstract Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT 1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT 1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas.
Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease
Authors: Anael Cain, Mariko Taga, Cristin McCabe, Gilad S Green, Idan Hekselman, Charles C White, Dylan I Lee, Pallavi Gaur, Orit Rozenblatt-Rosen, Feng Zhang, Esti Yeger-Lotem, David A Bennett, Hyun-Sik Yang, Aviv Regev, Vilas Menon, Naomi Habib, Philip L De Jager
Journal: Nature Neuroscience (2023)
Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes
Authors: Fangming Xie, Ethan J. Armand, Zizhen Yao, Hanqing Liu, Anna Bartlett, M. Margarita Behrens, Yang Eric Li, Jacinta D. Lucero, Chongyuan Luo, Joseph R. Nery, Antonio Pinto-Duarte, Olivier B. Poirion, Sebastian Preissl, Angeline C. Rivkin, Bosiljka Tasic, Hongkui Zeng, Bing Ren, Joseph R. Ecker, Eran A. Mukamel
Journal: Cell Genomics (2023)

Single-cell sequencing could help to solve the fundamental challenge of linking millions of cell-type-specific enhancers with their target genes. However, this task is confounded by patterns of gene co-expression in much the same way that genetic correlation due to linkage disequilibrium confounds fine-mapping in genome-wide association studies (GWAS). We developed a non-parametric permutation-based procedure to establish stringent statistical criteria to control the risk of false-positive associations in enhancer-gene association studies (EGAS). We applied our procedure to large-scale transcriptome and epigenome data from multiple tissues and species, including the mouse and human brain, to predict enhancer-gene associations genome wide. We tested the functional validity of our predictions by comparing them with chromatin conformation data and causal enhancer perturbation experiments. Our study shows how controlling for gene co-expression enables robust enhancer-gene linkage using single-cell sequencing data.
99mTc-MIBI SPECT/CT Evaluation of a Renal Collision Tumor
Authors: Adil A. Ali, Thangalakshmi Sivathapandi, Ritu Gupta, Viraj A. Master, Charles Marcus
Journal: Clinical Nuclear Medicine (2023)

Abstract Preoperative differentiation of oncocytomas from renal cell carcinoma (RCC) is often challenging. 99m Tc-MIBI imaging could play a potential role in differentiating oncocytoma from RCC, which in turn could guide surgical decision-making. We present the use of 99m Tc-MIBI SPECT/CT to characterize a renal mass in a 66-year-old man with a complex medical history, including history of bilateral oncocytomas. 99m Tc-MIBI SPECT/CT showed features suspicious of a malignant tumor, which was confirmed postnephrectomy as a chromophobe and papillary RCC collision tumor. This case supports 99m Tc-MIBI imaging for preoperative differentiation of benign versus malignant renal tumors.
Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression
Authors: Lin Qian, Na Li, Xiao-Chen Lu, Midie Xu, Ying Liu, Kaiyue Li, Yi Zhang, Kewen Hu, Yu-Ting Qi, Jun Yao, Ying-Li Wu, Wenyu Wen, Shenglin Huang, Zheng-Jun Chen, Miao Yin, Qun-Ying Lei
Journal: Nature Metabolism (2023)
Joint analysis of GWAS and multi-omics QTL summary statistics reveals a large fraction of GWAS signals shared with molecular phenotypes
Authors: Yang Wu, Ting Qi, Naomi R. Wray, Peter M. Visscher, Jian Zeng, Jian Yang
Journal: Cell Genomics (2023)

Molecular quantitative trait loci (xQTLs) are often harnessed to prioritize genes or functional elements underpinning variant-trait associations identified from genome-wide association studies (GWASs). Here, we introduce OPERA, a method that jointly analyzes GWAS and multi-omics xQTL summary statistics to enhance the identification of molecular phenotypes associated with complex traits through shared causal variants. Applying OPERA to summary-level GWAS data for 50 complex traits (n = 20,833-766,345) and xQTL data from seven omics layers (n = 100-31,684) reveals that 50% of the GWAS signals are shared with at least one molecular phenotype. GWAS signals shared with multiple molecular phenotypes, such as those at the MSMB locus for prostate cancer, are particularly informative for understanding the genetic regulatory mechanisms underlying complex traits. Future studies with more molecular phenotypes, measured considering spatiotemporal effects in larger samples, are required to obtain a more saturated map linking molecular intermediates to GWAS signals.
Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries
Authors: Ida Surakka, Kuan-Han Wu, Whitney Hornsby, Brooke N Wolford, Fred Shen, Wei Zhou, Jennifer E Huffman, Anita Pandit, Yao Hu, Ben Brumpton, Anne Heidi Skogholt, Maiken E Gabrielsen, Robin G Walters, Kristian Hveem, Charles Kooperberg, Sebastian Zöllner, Peter W F Wilson, Nadia R Sutton, Mark J Daly, Benjamin M Neale, Cristen J Willer
Journal: Cell Genomics (2023)

Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke (LAMC1, CALCRL, PLSCR1, CDKN1A, and SWAP70) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity (ABO), and one showed significant sex heterogeneity (ALDH2). The ALDH2 association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups.
A systematic review and meta-analysis of 90 cohort studies of social isolation, loneliness and mortality
Authors: Fan Wang, Yu Gao, Zhen Han, Yue Yu, Zhiping Long, Xianchen Jiang, Yi Wu, Bing Pei, Yukun Cao, Jingyu Ye, Maoqing Wang, Yashuang Zhao
Journal: Nature Human Behaviour (2023)
Increased 68Ga-FAPI Uptake in Benign Metastasizing Leiomyoma
Authors: Simin Wu, Jiayu Cai, Qi Chen, Jing Wu, Haojun Chen
Journal: Clinical Nuclear Medicine (2023)

Abstract Benign metastasizing leiomyomas (BMLs) are benign disseminated extrauterine tumors in patients with prior history of uterine leiomyomas and may occur years after hysterectomy. In this case, we presented 18 F-FDG and 68 Ga-FAPI PET/CT findings in a 37-year-old woman with benign leiomyoma metastasizing to lung and pelvis. The metastatic lesions demonstrated faint 18 F-FDG but elevated 68 Ga-FAPI activity, indicating the low level of glucose metabolism but excessive accumulation of activated fibroblasts in the BMLs. This case demonstrated that 68 Ga-FAPI PET/CT may be potentially useful in the evaluation of BMLs.
FDG-Avid But Pentixafor-Negative in EBV-Associated T-Cell Lymphoproliferative Disorders
Authors: Qiaoqiao Shu, Xubing He, Yue Chen, Liang Cai
Journal: Clinical Nuclear Medicine (2023)

Abstract An 18-year-old woman with intermittent fever, pancytopenia, abnormal liver function, and enlarged lymph nodes and hepatosplenomegaly was clinically suspected as hemophagocytic lymphohistiocytosis. 18 F-FDG PET/CT showed increased metabolism in multiple lymph nodes, which were highly suggestive of lymphoma. No increased CXCR4 expression in lymph nodes was demonstrated on 68 Ga-pentixafor PET/CT. Subsequent right neck lymph node biopsy pathology revealed EBV-associated lymphoproliferative disorders. Our case shows that 68 Ga-pentixafor PET/CT may have potential value in differentiating EBV-associated lymphoproliferative disorders from lymphomas.
Association between antidepressants with pneumonia and exacerbation in patients with COPD: a self-controlled case series (SCCS)
Authors: Rayan A Siraj, Charlotte E Bolton, Tricia M McKeever
Journal: Thorax (2023)

Objective To assess whether antidepressant prescriptions are associated with an increased risk of pneumonia and chronic obstructive pulmonary disease (COPD) exacerbation. Methods A self-controlled case series was performed to investigate the rates of pneumonia and COPD exacerbation during periods of being exposed to antidepressants compared with non-exposed periods. Patients with COPD with pneumonia or COPD exacerbation and at least one prescription of antidepressant were ascertained from The Health Improvement Network in the UK. Incidence rate ratios (IRR) and 95% CI were calculated for both outcomes. Results Of 31 253 patients with COPD with at least one antidepressant prescription, 1969 patients had pneumonia and 18 483 had a COPD exacerbation. The 90-day risk period following antidepressant prescription was associated with a 79% increased risk of pneumonia (age-adjusted IRR 1.79, 95% CI 1.54 to 2.07). These associations then disappeared once antidepressants were discontinued. There was a 16% (age-adjusted IRR 1.16, 95% CI 1.13 to 1.20) increased risk of COPD exacerbation within the 90 days following antidepressant prescription. This risk persisted and slightly increased in the remainder period ((age-adjusted IRR 1.38, 95% CI 1.34 to 1.41), but diminished after patients discounted the treatment. Conclusion Antidepressants were associated with an increased risk of both pneumonia and exacerbation in patients with COPD, with the risks diminished on stopping the treatment. These findings suggest a close monitoring of antidepressant prescription side effects and consideration of non-pharmacological interventions.
Primary Urethra Non-Hodgkin Lymphoma in a 46-Year-Old Man on FDG PET/CT
Authors: Weiwei Zhao, Peng Li, Yanmei Li, Yueming He, Jianwei Yang
Journal: Clinical Nuclear Medicine (2023)

Abstract Primary lymphoma of the male urethra is exceptionally rare. A 46-year-old man complained of low back pain, hematuria, and dysuria. Cystourethroscopy revealed a pale, annular thickening of the urethral mucosa. A biopsy revealed that the patient had diffuse large B-cell lymphoma. Before treatment, an 18 F-FDG PET/CT was used for staging. The urethra and left inguinal lymph nodes showed increased FDG uptake. The patient was then diagnosed with primary urethral lymphoma that had invaded the left inguinal lymph node.
Unexpected Solitary Subcutaneous Metastasis From Esophageal Carcinoma Revealed by MDP Bone Scintigraphy
Authors: Huipan Liu, Feifan Xiang, Yang Xie, Lin Liu, Yue Chen
Journal: Clinical Nuclear Medicine (2023)

Abstract A 60-year-old man with back pain underwent 99m Tc-MDP to evaluate bone metastases from newly esophageal carcinoma. No bone metastasis was found on the whole-body bone scan. Unexpectedly, subcutaneous metastasis revealed increased 99m Tc-MDP activity.
Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis
Authors: Grace Park, John A Haley, Johnny Le, Su Myung Jung, Timothy P Fitzgibbons, Ekaterina D Korobkina, Huawei Li, Shelagh M Fluharty, Qingbo Chen, Jessica B Spinelli, Chinmay M Trivedi, Cholsoon Jang, David A Guertin
Journal: Nature Metabolism (2023)
Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis
Authors: Debarati Mukherjee, Rebecca A. Previs, Corinne Haines, Muthana Al Abo, Patrick K. Juras, Kyle C. Strickland, Binita Chakraborty, Sandeep Artham, Regina S. Whitaker, Katherine Hebert, Jake Fontenot, Steven R. Patierno, Jennifer A. Freedman, Frank H. Lau, Matthew E. Burow, Ching-Yi Chang, Donald P. McDonnell
Journal: Cancer Research (2023)

Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.
Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma
Authors: Guillaume Davidson, Alexandra Helleux, Yann A. Vano, Véronique Lindner, Antonin Fattori, Marie Cerciat, Reza T. Elaidi, Virginie Verkarre, Cheng-Ming Sun, Christine Chevreau, Mostefa Bennamoun, Hervé Lang, Thibault Tricard, Wolf H. Fridman, Catherine Sautes-Fridman, Xiaoping Su, Damien Plassard, Celine Keime, Christelle Thibault-Carpentier, Philippe Barthelemy, Stéphane M. Oudard, Irwin Davidson, Gabriel G. Malouf
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor–NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial–mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. Significance: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.